August 12, 2009

A team at Joslin has been looking for more MODY genes and has found one they say should be added to the six currently tested for. This gene is named BLK. One of its many functions is to trigger insulin production.

MODY is believed to cause 2% to 3% of all cases of diabetes. As reported there are currently eight genes known to cause MODY, but these account for only 85% of those whose family histories are suggestive. Joslin's researchers are looking for the genes that cause the other 15%.

I had volunteered for this study but was unable to participate because one requirement is that participants have a fairly large number of relatives with diabetes. My extended family was too small to qualify.

Unfortunately, when I contacted them two years ago, the Joslin researchers were not willing to share findings with the study subjects. So whatever the benefits of this study for science, it won't help those of you with clear-cut MODY family histories who don't test for the known genes.

Because I maintain this MODY page I get a lot of mail from people diagnosed with Type 2 Diabetes who are not fat who are wondering if they have MODY. Most of them do not. Slow onset autoimmune diabetes (LADA) is much more common than MODY and is a much more likely cause for high blood sugars in normal weight people in their 30s and older.

One key thing to understand about MODY is that if you have it, you will have had abnormal blood sugars all your life in some form or other. Blood sugar problems that emerge suddenly and deteriorate over a year or two are much more likely to be autoimmune in nature. The blood sugars associated with MODY tend to stay relatively stable.

So if you are a thin or normal weight person diagnosed with Type 2 diabetes, don't even consider MODY as a possible cause for your diabetes unless you have had a full set of Type 1 antibody tests that are negative, a normal fasting C-peptide test (several forms of MODY only affect insulin secretion in response to meals), have no history of any other autoimmune disease, and have a life long history suggestive of abnormal glucose tolerance.

Unfortunately, as you can see from the reporting of this story in Medical News Today, the only reason scientists are working on MODY is because they hope to find genes implicated in Type 2 diabetes. Once they find a new gene that affects insulin secretion they are done. This means that once you are diagnosed with MODY by a gene test you rarely will be able to find out anything further about the probable course of the kind of MODY you have or even about the best treatments.

This is because all the money in diabetes is in treating the millions with Type 2 and the funding goes into studies that could turn into blockbuster drugs for Type 2.

Meanwhile we people with MODY have to muddle along on our own, often without the help of doctors who have any knowledge of what MODY is.

One thing I would like to make clear before I leave this discussion is this: It is not true that "MODY is simpler to diagnose and treat than the other forms of diabetes," as stated in the Medical News Today article. In fact, most of us with MODY go through years of misdiagnosis and inappropriate treatment.

Each genetic form of MODY is different, and they each require different treatment approaches. Finding the one that works for your own specific case can take a lot of work and because prescription drugs are involved you will need the support of an endocrinologist willing to work with you.

Since many endos have zero knowledge about MODY, many people with MODY get the same miserably poor treatment as the rest of the Type 2 community, and end up with the 8%+ A1cs that guarantee they will develop complications.

Because contrary to what you may read online, every form of MODY causes complications, it is only a matter of which one. MODY-2 (GCK) doesn't cause neuropathy or retinopathy, just fatal heart attacks, often striking the young. The HNF MODYs cause blood sugars high enough to produce all the classic -pathies and the sulfonylurea drugs often prescribed for them do not give the normal blood sugars that will prevent these complications. Only meal-time insulin can do this though some people with MODY-3 respond very well to Byetta. The gene responsible for MODY-3 can also cause congenital kidney malformations that lead to an early death if not diagnosed correctly.

So if you are diagnosed with MODY in any form, you will have to fight very hard to get appropriate treatment. If you just rely on your doctor and believe that MODY is "easy to treat" and that A1cs near 7% are all you need to attain, you are deluding yourself.

I have written to the researchers who identified this latest MODY gene to see if I can find out anything more about BLK MODY, but my guess is that having found the gene they will move on and those who have the gene will be left in the dark as to what it means and how to best treat it.

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comments:

I always prick up my ears when i read about "new" genes being found. Everything that is wrong with me is wrong with some but not all people in one side of the family or the other. None of them seem to be monogenic though as different individuals have different subsets of symptoms - most folks on one side have some but seldom all symptoms of IR/metabolic syndrome and the diabetics are all skinny males, so there's something weird but not one of the "weirds" that have yet been discovered.

Over time I've met not a few other unrelated individuals with a similar pattern - BG problems often including reactive hypoglycemia starting in childhood but progressing slowly, suggesting a Phase 1 insulin malfunction long before Phase 2 is affected - and often unconnected to overweight - BUT the problem with all this research as you write is getting the information out there. My symptoms were mainly blown off as "neurotic" or "made up" but of course if they had been correctly identified all that would have happened was that I would have been put on a high carb low fat diet earlier than I actually was. So I'd probably be significantly worse off by now.

I imagine this must occur with most identifiable MODYs too unless you are lucky enough to find a clueful Endo.

I relate a lot to what you are going through. Via research I've discovered leptin replacement is necessary for me to avoid numerous unpleasant side effects both acute and long term (whether due to being heterozygous for cogenital leptin deficiency or simply acquired damage to my fat tissue after massive weight loss, the fact is I make almost no leptin naturally at this point in time).

I am presently in a clinical research trial where I have access to leptin replacement at normal physiologic doses (I see the joslin diabetes center all the time ho ho, drug research capital of america) and it's kinda depressing for me because I know ultimately these researchers don't give a crap about my condition or people like me because we aren't profitable. There just aren't enough people LIKE ME to make this profitable.

They are just using me to study the effects of leptin replacement in partial leptin deficiency, with the ultimate goal being to 1) invent some new oral drug that could slow osteoporosis in the elderly or 2) help weight loss in garden variety fat people who refuse to follow an insulin balancing diet or 3) assist infertile thin women conceive. These drugs they hope to develop, oral drugs which would undoubtedly have side effects because it would be unnatural to our physiology (but undoubtedly the patents will have expired by then, ha ha ha all the way to the bank). There is not and never will be a mass produced leptin hormone available for people like me... we're rare, and it's just not life or death critical. And that is so depressing. I feel so good with it, and I know in 6 months I"ll never be able to use it again.

It's sometimes a curse being so aware of things like this. It would be easier to just be ignorant and blame myself for how I feel and my hunger and such.

I am so impressed by your research into this rare form of diabetes. Most of us are used to thinking "either type 1 or type 2" when the reality is vastly more complicated.

I was wondering if you had any knowledge of disorders which seem to cause a PRIMARY HYPERSECRETION (as in, not secondary to glucose intolerance or hyperglycemia). I believe I may have a defect in how insulin is regulated with a tendency toward postprandial hypersecretion and it is probably not related to hyperglycemia or glucose intolerance. My fasting sugar is always low (70-60) and my post meal readings (low carb) are always under 110, often 90-100. But I have a history of severe obesity (early onset), reactive absolute and relative hypoglycemia, PCOS (very early onset), and I rapidly develop signs of PCOS acanthosis of skin when I let my eating slip. Even on a very good low carb diet I have hypoglycemia at times after eating. All of this seems to suggest the problem is an abnormality in deactivating insulin, or a tendency to make too much insulin, without hyperglycemia or glucose intolerance being the problem. There isn't much out there about people like me, I assume this is probably fairly rare (most PCOS/obese people are hyperglycemic at least some of the time... I don't ever seem to become hyperglycemic and my glucose falls rapidly and sharply and easily... the fact I am not glucose intolerant and my body burns sugar normally is probably the reason why I had such an easy time losing weight once post-meal hyperinsulinemia was controlled by the avoidance of glucose-rising food).

I would like to know where I can find more info about MODY 3, which I am almost certain that I have. I had my first glucose tolerance test when I was 9 years old; fasting was normal, post went up into the low 300's. Doctors repeated the test every year for the next six years, results were always the same. I was called "borderline diabetic" for the next twenty years. Had gestational diabetes requiring insulin throughout during both pregnancies. My fastings have always been normal, my posts abnormal. By the time I was 35, I had aquired complications of long-term untreated diabetes, including neuropathy in my hands and feet. I was finally treated for "Type 2" diabetes. I've been taking oral meds since then (eight years) and have recently added Byetta. Oh, I also have two uncles and an aunt on my mother's side with the same diagnosis. My doctors are usuallay clueless and treat me like a guinea pig. My current doctor seems open to learning more about MODY and working with me. Can you please lead me to more info? Thanks!

Unfortunately, doctors have done very little study into the treatment of MODY-3, as they are more interested in finding genes that would apply to Type 2.

The main thing is to control the post meal blood sugars. Insulin, Byetta, and sulfonylurea drugs like Amaryl and the drug Prandin all all worth a try. Use very low doses of the Amaryl when you test it and work up. 1/2 of the 1 mg tablet is the recommended starting dose. Some people find Amaryl makes them too hungry. Prandin at normal doses might work better as it only works at meals.

Byetta and the oral drugs bridge the flaw that stops mealtime secretion. Insulin injections just supply the insulin needed. If you use insulin, study the books written for Type 1s, like Using Insulin by John Walsh and ignore the information about basal insulin as you may still have normal basal secretion.

Jenny, thanks for the info. It is so good to know that I am not the only one who has had such difficulty with diagnosing and treating my diabetes. I would like to ask for your opinion on my current meds regimen. For the past 3-4 years, I have been taking Amaryl (4mg in the morning and 2 mg in the evening), metformin (2000mg) in the evening, and have recently added Byetta (5 mcg before dinner). My doctor tried to back me off of the metformin by cutting my dose in half a month after I began the Byetta, but my fasting bg rose and I experienced extreme fatigue, so I am back on the above doses. She is concerned about the long-term affects of the oral meds. Would I be better off switching to insulin or trying to stick with this hodge-podge of meds. I know that you are not an MD, but I do value your opinion. Thanks! (BTW - I have always been petite, 5'4" and under 120 lbs, and any change in doses has a drastic affect on my body.)

I'm not a doctor. So all I can do is tell you that I and several other people I've heard from who have MODY do very well on low doses of fast-acting insulin at meal time.

HOWEVER, it takes serious study to learn how to use fast acting insulin to get tight control. You will have to learn the exact carb content of every thing you eat AND weigh and measure portions until you get the hang of it. Then you have to experiment to learn how many grams of carbohydrate are covered by a unit of Novolog, Humalog, or Apidra.

I have heard from people who have done very well on Byetta with diagnosed MODY-3, too, who say they like it better than insulin.

There is no harm in trying a different regimen if you do it with your doctor's support. Read Using Insulin or DR. Bernstein's Diabetes Solution to get the hang of how insulin is used with meals. Then try the insulin for a month and see how it works for you.

Dr. Hattersley in England prefers to use the sulfonylurea drug saying that it leads to better long term outcomes BUT he uses one that is different (and sounds better) than what we have in the US. The drug he uses is not available here. So his advice has to be taken with that in mind.

The benefit of stimulating insulin secretion in MODY is that you do get natural C-peptide being produced along with it, which may help fight complications. But there may be negative heart effects with Amaryl. Hard to say from the evidence.

Personally what I do is eat close to no carb meals which don't require insulin and then use insulin with higher carb meals once or twice a day. That works for me. I use metformin because it keeps me from gaining weight which I do extremely easily now that I'm old, though it doesn't make a significant difference in my blood sugar fasting or post-meal.

Laura, if the metformin has such an effect that suggests you have insulin resistance, not normally a factor in MODYs, but a familial factor in what I suffer from. I also suffer from an increase in the IR from BG spikes: if I concentrate I can feel this starting to cut in with BG around 120 and it's noticeable at 150 and upwards, too mcuh glucose in my blood but the muscles can't utilise it. IMO this is obviously genetic but not monogenic considering the familial distribution.

It's responded remarkably well to reducing carbs to around 60g/day and utilising fat (especially saturated fat) protein and low carb veggies as energy sources. Check your lipids (especially the trigs/HDL ratio) as an indicator of IR

My experience is that these "rare" variants are not so much rare as underdiagnosed. I also suspect despite the IR we generate adequate leptin, would be useful if I could email some to ItsTheWoooo . . .

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I was diagnosed with diabetes in 1998. Since then I've kept my A1cs in the 5.0-6.0% range using the techniques you'll find explained at The main Blood Sugar 101 Web Site, where you'll also find extensive discussion of the peer-reviewed research that backs up the statements you read here.

I've also published two books on related subjects, Blood Sugar 101: What They Don't Tell You About Diabetes, which was an Amazon Diabetes bestseller for 3 years and Diet 101: The Truth About Low Carb Diets.